Abstract

Transient neonatal diabetes mellitus (TNDM) is diagnosed in the first 6 months of life, with remission in infancy or early
childhood. For ∼50% of patients, their diabetes will relapse in later life. The majority of cases result from anomalies of
the imprinted region on chromosome 6q24, and 14 patients with ATP-sensitive K+ channel (KATP channel) gene mutations have been reported. We determined the 6q24 status in 97 patients with TNDM. In patients in whom no
abnormality was identified, the KCNJ11 gene and/or ABCC8 gene, which encode the Kir6.2 and SUR1 subunits of the pancreatic β-cell KATP channel, were sequenced. KATP channel mutations were found in 25 of 97 (26%) TNDM probands (12 KCNJ11 and 13 ABCC8), while 69 of 97 (71%) had chromosome 6q24 abnormalities. The phenotype associated with KCNJ11 and ABCC8 mutations was similar but markedly different from 6q24 patients who had a lower birth weight and who were diagnosed and remitted
earlier (all P < 0.001). KATP channel mutations were identified in 26 additional family members, 17 of whom had diabetes. Of 42 diabetic patients, 91%
diagnosed before 6 months remitted, but those diagnosed after 6 months had permanent diabetes (P < 0.0001). KATP channel mutations account for 89% of patients with non-6q24 TNDM and result in a discrete clinical subtype that includes
biphasic diabetes that can be treated with sulfonylureas. Remitting neonatal diabetes was observed in two of three mutation
carriers, and permanent diabetes occurred after 6 months of age in subjects without an initial diagnosis of neonatal diabetes.

Footnotes

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